Validation of a Handheld 6-Lead Device for QT Interval Monitoring in Resource-Limited Settings

Key Points Question What is the diagnostic accuracy and feasibility of a handheld 6-lead electrocardiographic (ECG) device for QTc interval measurement in a resource-limited setting? Findings In this diagnostic study, 2070 longitudinal reference standard 12-lead ECG measurements and 2105 6-lead measurements were evaluated in a nested prospective cohort of 191 participants in a tuberculosis trial. At a QTc interval threshold of 500 milliseconds, the handheld 6-lead device had a high negative predictive value of 99.8% but a low positive predictive value of 16.7%. Meaning This study suggests that a 6-lead ECG device is an effective triage test and could reduce the need to perform 12-lead ECG monitoring in resource-limited settings.


Statistical analyses
Heart rate, QT interval, and QTc were abstracted from reference standard 12-lead (i.e., manually read Clario measurements, as above) and automated/algorithmic handheld 6-lead ECG measurements.QTc was calculated using the Fridericia formula (QTc = QT / RR 1/3 ); 1 we further assessed a population-specific (QTcN) 2 and Bazett's (QTcB = QT / RR 1/2 ) correction method (eTable 1).Mean increase in QTc was measured using a linear mixed effects regression model of QTc on clinic visit with random intercepts by participant.Clinic visits with fewer than triplicate 12-lead reference standard QTcF measurements were excluded from the primary analysis.
Visit-level triplicate (or more, if more than three measurements were available) QTcF measurements for both devices were averaged, compared, and illustrated using scatter plots. 3Outlier 12-lead reference standard QTcF measurements (>40ms range between triplicate measurements) were rechecked and re-analyzed if appropriate by an adjudicating cardiologist (co-author, RK).In accordance with prior studies, 4,5 we reported the maximum mean change in QTc from baseline.
Quantitative inter-modality agreement was measured using Bland-Altman plots. 6The k-medoids clustering technique was used to group the results of the Bland Altman plot into two clusters.We utilized this method instead of the k-means to reduce distortion from outliers.We used the Within-Sum-of-Squares (WSS) or Elbow method 7,8 to identify the ideal number of clusters; this method is used in cluster analysis to determine the optimal number of clusters by identifying the point at which the addition of another cluster does not significantly improve the fit of the model, visually resembling an "elbow" on the plot.0][11] We assessed the repeatability of each modality using a linear mixed-effects model fit to the numerical QTcF values.Such models allow global estimation of within-person standard deviation (SD) optimally weighted for the correlation structure of the repeated measurements. 12,13Assuming that 95% of measurements are located within 1.96 SDs, the "normal expected range" of within-subject test repeatability can be calculated by expressing this SD as a percentage of the individual's mean QTcF.Thus, given an underlying 'true' mean test result, linear mixed effect models estimate the expected variability that will occur with repeat measurement; the resultant standard deviation is thus an estimate of how close a given measurement is to the true value.As test-retest differences were not normally distributed, the 12-lead and 6-lead datasets were verified of having 95% of differences contained within 1.96 SDs of their means by a resampling procedure using 10,000 bootstrap iterations.We conducted a qualitative survey of nurses who performed the 12-lead and handheld 6lead measurements assessing ease of use and preferences for use in clinical workflow.All P values were twosided with alpha=0.05 as the significance level.Data analysis was performed using Python 3.   The k-medoids clustering technique was used to group the results of the Bland Altman plot into two clusters.We utilized this method instead of the k-means to reduce distortion from outliers.To identify that two clusters were the ideal number of clusters, we used the Within-Sum-of-Squares/Elbow method.The cluster centers are illustrated by two blue circles, and the bias (-3.7ms) from the Bland Altman analysis is shown by a horizontal blue line.The cluster centers can clearly be seen to be above and below the bias, indicating that the 6-lead tended to underestimate and overestimate QTcF when the actual QTcF is low or high respectively.(1) 60 site visits had no measurements taken using the 6-lead ECG handheld device, while 7 visits had no available measurements with the 12-lead ECG.
(2) 1 site visit had more than 3 measurements taken using the 12-lead ECG.22 site visits had more than 3 measurements taken using the 6-lead ECG.All (4/4; 2 nurses per site) BEAT-TB tuberculosis nurses queried responded to the survey.Obtaining ECG measurements for RR-TB patients were noted to be time-consuming by all nurses.None reported difficulty with using the 6-lead device or the smartphone-based application.Most (75%) were more satisfied with the 6-lead ECG testing relative to the 12-lead ECG, and all were confident in the results provided and felt that the 6-lead device would improve clinic workflow.Most (75%) recommended the 6-lead over conventional 12-lead device.One nurse noted that a patient's condition may impact ability to measure using the 6-lead device.a Normal expected range of within-subject variability, estimated using linear mixed effects models.This range about an individual's true value (the value in absence of repeatability variability) would include 95% of repeat measurements for that individual at a single visit.

Duplicate and
b Repeatability is the precision of a test when replicated under identical apparent conditions (e.g., same laboratory, operator, apparatus, minimal time interval); a measure of the inherent random error associated with a test.
Given an estimated 6-lead QTcN or QTcB of 499 ms (just below test cutpoint for clinical action) and a normal expected range of within-subject variability of +/-49.8ms (i.e., two repeatability standard deviations), 95% of subjects demonstrate variability between 449 and 549 ms.Thus, the low positive zone for the 6-lead device is defined as the interval (500-549 ms) within which a positive result could be expected to revert to negative on retest based solely on the inherent variability of the test.
c The intraclass correlation coefficient is defined as the ratio of the within-person variability to the total variability; here, this would be interpreted as the proportion of total variance that is between (rather than within) individuals.

eFigure 1 .
The 6-Lead ECG in Use A, This panel illustrates the hand-held AliveCor KardiaMobile 6L from the bottom and top.B, This panel shows one of the recommended methods of using the six-lead device.Both thumbs are placed on the two top electrodes and the third bottom electrode is in contact with the skin above the left ankle (the bottom electrode can also be in contact with the skin above the left knee).

eFigure 2 .
Bland-Altman Plot of QTcF Agreement Between the Handheld 6-Lead ECG Device and Reference Standard 12-Lead ECG Bland-Altman analysis for the triplicate averaged QTcF measurements (6-lead vs. 12-lead) across full range of QTcF values for 489 individual comparisons across 170 participants showed a mean difference of -3.7 milliseconds (ms) and 1.96 standard deviations (1.96 SD) of ± 46.3ms.The lower and upper limits of agreement (mean difference ± 1.96 SD) are +43ms and -50ms, respectively.eFigure 3. k-Medoids Cluster Analysis of the Differences Between the 12-Lead and Handheld 6-Lead ECG Measurements at Each Site Visit Reasons for Indeterminate QTcF Measurements Over the study duration, 2,070 and 2,015 total 12-lead and 6-lead ECG assessments were made, 2.1% and 11.7% of which were indeterminate, respectively.The table reflects all indeterminate QTcF measurements, regardless of number of valid measures ultimately obtained at individual clinic visits.Number of Conventional 12-Lead ECG and 6-Lead ECG Measurements Taken at a Single Site Visit

you have any reasons for not taking or being able to take a measurement with the KardiaMobile 6L following the conventional 12-lead ECG ? Please explain.
Contingency Tables of 6-Lead QTcF vs Reference Standard 12-Lead at 500ms and 480ms Diagnostic Cutpoints TN = True negative; FN = False negative; TP = True positive; FP = False positive.The contingency tables display the number of true negative, false negative, true positive, and false positive measurements with the triplicate averaged 12-lead ECG QTcF measurements as the reference standard and all handheld 6-lead ECG QTcF measurements as the predictor.Relative to the primary analysis shown in Figure1(including only triplicate or greater 6-lead measurements), correlation and cutpoint classification were less favorable when fewer than triplicate 6-lead measurements were analyzed against reference standard triplicate 12-lead ECG QTcF. the triplicate averaged 12-lead ECG QTcF measurements as the reference standard.Differential effects of sex, age (less than 50 compared to equal to or over 50), and BMI (underweight [<=18.5]compared to normal [>18.5 and <25]) are shown.There were no positive measurements among female participants at the 500 ms cutpoint, but PPV among males was 33.3% (95% CI, 6.6% to 78.0%).Among participants 50 years of age and older, there was only one measurement above 500ms (false positive) by the 6-lead device and none by the 12-lead.PPV in those under the age of 50 was 20% (95% CI, 8.6% to 39.9%).There were three false positives among BMI underweight participants and no true positives.Among normal weight participants, there was one true positive measurement and no positive measurements by the 6-lead.Negative predictive values were similar (98.6-100%) across all groups.Repeatability of the 12-Lead ECG QTcF Interpretation at a 500 Millisecond Cutpoint 'Positive' results are measurements greater than 500 ms.Indeterminate results have no QTcF measurements available.Three additional clinic time points (not shown) had only one attempt; all of these attempts had 'Negative' (i.e., QTcF <500 ms) results.One time point had no 12-lead measurements but did have 6-lead measurements and one visit had no measurements from either device.Visits with concordant measures were 98.8% (643/651) of all visits with at least three determinate 12-lead measurements.Repeatability of the 6-Lead ECG QTcF Interpretation at a 500 Millisecond Cutpoint Positive results are measurements above a 500 ms cutpoint.Indeterminate results have no QTcF measurements available.Thirty-seven visits had no 6-lead measurements but did have 12-lead measurements and one visit had no measurements from either device.Visits with concordant measures were 92.9% (487/524 visits) of all visits with at least three determinate 6-lead measurements.Response 1 "12 lead is time consuming since participant has to undress so 6L would assist in patient flow."Response 2 "Will definitely improve the clinic workflow."Response 3 "Reduce patient clinic time."Response 4 "It would assist with time constraints making workflow much faster, also patient not having to undress especially when it's very cold weather."Did eTable 4. Contingency Tables of 6-Lead QTcF vs Reference Standard 12-Lead at 500ms Cutpoint by Sex, Age, and BMI BMI = body mass index The contingency tables display the number of true negative, false negative, true positive, and false positive measurements with

12-lead ECG 6-lead ECG Individual device parameters -QTcN
Handheld 6-Lead and Reference Standard 12-Lead ECG QTcN and QTcB Device-Specific Parameters SD = standard deviation; ms = milliseconds; ICC = Intraclass correlation coefficient.Individual device parameters were calculated for each device from visits including triplicate averaged measurements, regardless of measurement availability for the other device.All statistics except for N are presented in milliseconds.